Phase 1/2 selumetinib plus trastuzumab deruxtecan targets KRAS-mutant, HER2-expressing pancreatic cancer

This NCI-sponsored Phase 1/2 study combines selumetinib (AZD6244, AstraZeneca), an oral MEK1/2 inhibitor, with trastuzumab deruxtecan (T-DXd, Daiichi Sankyo/AstraZeneca), a HER2-directed antibody-drug conjugate carrying a topoisomerase I inhibitor payload, in unresectable or metastatic pancreatic ductal adenocarcinoma. Tumors must harbor a KRAS mutation and express HER2 by immunohistochemistry, using gastric-cancer scoring criteria: IHC 2+ or above is allowed in dose escalation, while Phase 2 uses protocol-defined decision rules.

The Phase 1 portion establishes tolerability and a recommended dose before evaluation of preliminary activity. The biomarker requirement is HER2 protein expression, not necessarily HER2 gene amplification. The scientific rationale is to combine HER2-directed cytotoxic delivery with suppression of MAPK signaling downstream of KRAS. This is an experimental biomarker-selected strategy in a disease where systemic chemotherapy remains central; activity and combination safety, including toxicities associated with each component, require prospective evaluation.